Nutraceutical compositions comprising epigallocatechin gallate and raspberry ketone

ABSTRACT

Compositions comprising epigallocatechin gallate and 4-(4-hydroxyphenyl)-2-butanone may be used for the treatment or prevention of obesity or conditions associated with obesity such as non-insulin-dependent diabetes mellitus (NIDDM, type II) and syndrome X. The compositions may find use in the nutritional field as a supplement to food and beverages, as well as as a pharmaceutical formulation.

The present invention relates to novel nutraceutical compositionscomprising epigallocatechin gallate (hereinafter: EGCG) and raspberryketone (4-(4-hydroxyphenyl)-2-butanone, hereinafter: RK). Morespecifically, the invention relates to novel nutraceutical compositionsfor the treatment or prevention of obesity, or conditions associatedwith obesity such as non-insulin-dependent diabetes mellitus (NIDDM,type II) and syndrome X. In another aspect, the invention relates to theuse of EGCG and RK in the manufacture of a nutraceutical composition forthe treatment or prevention of obesity or conditions associated withobesity such as non-insulin-dependent diabetes mellitus (NIDDM, type II)and syndrome X. In yet another aspect, the invention relates to a methodof treatment or prevention of obesity or conditions associated withobesity such as non-insulin-dependent diabetes mellitus (NIDDM, type II)and syndrome X, which comprises administering to a subject in need ofsuch treatment an effective amount of a combination of EGCG and RK.Furthermore, the present invention provides a method for treating,ameliorating or preventing obesity, or other conditions associated withobesity such as non-insulin-dependent diabetes mellitus (NIDDM, type II)and syndrome X through the administration of EGCG and RK.

The composition is particularly intended for the treatment or preventionof obesity, and for the prevention of NIDDM in those individuals thatare at high risk, e.g., that are overweight or have impaired glucosetolerance.

The composition comprises a combination of EGCG and RK, which havedifferent mechanisms of action on glucose and fat uptake as well asexcretion, hepatic glucose production, and energy expenditure. Thus, thecombination is providing additive and/or synergistic effects for thetreatment or prevention of obesity.

The term nutraceutical as used herein denotes usefulness in both thenutritional and pharmaceutical field of application. Therefore, thenovel nutraceutical composition can be used as a supplement to food andbeverages, and as pharmaceutical formulation for enteral or parenteralapplication, which may be solid formulations such as capsules ortablets, or liquid formulations such as solutions or suspensions. Aswill be evident from the foregoing, the term nutraceutical compositionalso comprises food and beverages containing EGCG and RK as well assupplement compositions containing both active ingredients.

Even though awareness of the association between obesity and healthproblems is longstanding the prevalence of obesity has grown to epidemicproportions during the last few decades. Currently, more than 50% of theUS population are overweight and approximately 20% are considered to beobese or extremely overweight. The prevalence of obesity is stillincreasing rapidly not only in industrialized countries. Obesity willbecome one of the most important public health problems innonindustrialized countries, particularly in those undergoing economictransition. The World Health Organization (WHO) has estimated that in2025, approximately 300 million people will be obese.

Obesity is the most important risk factor for the onset of NIDDM.Moreover, being moderately overweight is also closely associated to theonset of NIDDM. The WHO calculated that the prevalence of patients withNIDDM could be reduced by as much as 64% in US men and 74% in US women,if there were no overweight and obese subjects. NIDDM is associated withincreased risk for mirco- and macrovascular diseases, includingnephropathy, and neuropathy.

Obesity has the strongest impact on cardiovascular risk profile amongall other risk factors. Obese subjects are at high risk for increasedblood pressure and unfavorable lipid profile such as decreased highdensity lipoprotein (HDL) cholesterol levels and increased low densitylipoprotein (LDL) cholesterol as well as triglyzeride levels. Weightloss was demonstrated to reduce blood pressure and to improve lipidlevels and a high body weight is associated with increasedcardiovascular mortality.

Furthermore, obesity is an established risk factor for endometrialcancer. There is evidence for a possible relationship between obesityand breast, kidney, colon, prostate, and gallbladder cancer. Not onlythat obesity causes cancer, it might also influence cancer detection dueto a lack in compliance for screening programs and also due to detectionproblems caused by adipose tissue. In addition, obesity is one of themost important risk factors for osteoarthritis in knee and hip jointsand associations with herniated lumbar intervertebral disc, lower backpain, and chronic neck pain have been suggested.

Obstructive sleep apnea and shortness of breath are typical respiratoryconsequences of obesity.

Thus, the treatment or prevention of obesity would reduce the prevalenceof a variety of chronic diseases and acute adverse events. Typically,the treatment of obesity involves dietary and lifestyle interventions.However, the compliance of patients to such programs is low. Patientscommonly do not recognize obesity as a disease and are therefore lesslikely to respond to lifestyle changes. Furthermore, evenmultidisciplinary approaches including dietary measure, increase inphysical activity and behavior modification do not provide asatisfactory success rate, particularly if long-term results areconsidered.

Therefore, the use of weight lowering agents has been proposed as a moreeffective treatment choice for obesity. However, the development ofdrugs like amphetamines was not only disappointing in terms of efficacybut turned out to cause a number of partially severe adverse effects,which finally led to the withdrawal of most of these compounds.Serotoninergic drugs such as fenfluramine and dexfenfluramine were alsoassociated with severe adverse effects and as a consequence withdrawnfrom the market. Other treatments like the noradrenergic/serotoninergicdrug sibutramine have side effects ranging from dry mouth, insomnia,anorexia, constipation, and increase in heart rate as well as bloodpressure. Lipase inhibitors like orlistat cause fecal urgency, oilyspotting, fatty stool, flatus, discharge, increased defecation and fecalincontinence, occurring with a frequency of 10 to 30%.

These facts illustrate that there is need for a safe and effectivenutritional supplement with minimal side effects for the treatment andprevention of obesity. Obese subjects are interested in substances thatthey consider being natural or plant derived food ingredients withoutmajor side effects. These compounds could be used as adjuvant treatmenttogether with dietary intervention and increased physical activity.Furthermore, obesity is a complex and multifactorial disease and thus, acombination therapy is an attractive and feasible approach to reduce thebody weight of a variety of obese patients.

Epigallocatechin gallate (EGCG) is the major catechin found in greentea. The beneficial health effects of green tea have been mainlyattributed to the catechins. In mice, tea catechins reduced diet-inducedweight gain, visceral fat mass, as well as plasma leptin, triglyceride,and glucose levels. Tea catechins are also known to increase energyexpenditure in rats. In humans, tea catechins have been shown to reducebody weight, visceral fat mass, and plasma cholesterol, insulin, andglucose levels. Green tea extract was shown to significantly increaseenergy expenditure and fat oxidation in healthy men. Furthermore, it wasshown in brown adipose tissue of rats that EGCG stimulates metabolicactivity and oxygen consumption. Additionally, several animal studiesdemonstrated that catechins inhibited cholesterol absorption and loweredplasma cholesterol levels. In turn, epicatechins increase the fecalexcretion of cholesterol and total lipids. Therefore, EGCG has anantiobesity effect, through a stimulation of thermogenesis and/or analtered fat absorption.

Raspberry ketone (4-(4-hydroxyphenyl)-2-butanone, RK) is one of thecharacter impact components of raspberry flavor. The compound has beenidentified as the free ketone and as glucoside in the berries. Thecompound accumulates rapidely during the ripening of rasberry fruits. RKor its glucoside are not only found in the raspberry fruit but also inrhubarb roots, cranberries and the needles of pine.

The nutraceutical composition of the present invention contains EGCG inan amount sufficient to administer to a subject a dosage from about 0.01mg to about 60 mg per kg body weight per day, preferably from about 0.1mg to about 10 mg per kg body weight per day. Thus, if the nutraceuticalcomposition is a food or beverage the amount of EGCG contained thereinis suitably in the range from about 0.3 mg per serving to about 1250 mgper serving. If the nutraceutical composition is a pharmaceuticalformulation such formulation may contain from about 1 mg to about 4000mg per solid dosage unit, e.g., per capsule or tablet, or acorresponding dosage in a liquid formulation, or from about 1 mg perdaily dose to about 4000 mg per daily dose. In a preferred aspect of theinvention, the nutraceutical composition of the present inventionfurther contains rasberry ketone (RK). The amount of RK in thecomposition may be such to provide a daily dosage from about 0.01 mg perkg body weight to about 60 mg per kg body weight of the subject to whichit is to be administered. A food or beverage suitably contains about 0.3mg per serving to about 1250 mg per serving of RK. If the nutraceuticalcomposition is a pharmaceutical formulation such formulation may containRK in an amount from about 1 mg to about 4000 mg per dosage unit, e.g.,per capsule or tablet, or from about 1 mg per daily dose to about 4000mg per daily dose of a liquid formulation.

-   Dosage ranges (for a 70 kg person): Epigallocatechin gallate (EGCG):    1 to 4000 mg/day;-   Raspberry ketone (RK): 1 to 4000 mg/day.

The following examples illustrate the invention further.

A. Pharmaceutical compositions may be prepared by conventionalformulation procedures using the ingredients specified below:

EXAMPLE 1

soft gelatin capsule

Soft gelatin capsules can be prepared by conventional procedures usingingredients specified below: Epigallocatechin gallate (EGCG) 100 mgRaspberry ketone (RK) 100 mgOther ingredients: glycerol, water, gelatine, vegetable oil

EXAMPLE 2

hard gelatin capsule

Hard gelatin capsules are prepared by conventional procedures usingingredients specified below: Epigallocatechin gallate (EGCG) 100 mgRaspberry ketone (RK) 100 mgOther ingredients:

-   Fillers: lactose or cellulose or cellulose derivatives q.s.-   Lubricant: magnesium sterate if necessary (0.5%)

EXAMPLE 3

Tablet

Tablets can be prepared by conventional procedures using ingredientsspecified below: Epigallocatechin gallate (EGCG) 50 mg Raspberry ketone(RK) 50 mg

Other ingredients: microcrystalline cellulose, silicone dioxide (siO2),magnesium stearate, crosscarmellose sodium

B. Food items may be prepared by conventional procedures usingingredients specified below:

EXAMPLE 4

Soft Drink with 30% juice Typical serving: 240 ml Active ingredients:Epigallocatechin gallate (EGCG): 0.3-1250 mg/per serving Raspberryketone (RK): 0.3-1250 mg/per serving

I. A Soft Drink Compound is prepared from the following ingredients:Juice concentrates and water soluble flavours [g] 1.1 Orange concentrate60.3 °Brix, 5.15% acidity 657.99 Lemon concentrate 43.5 °Brix, 32.7%acidity 95.96 Orange flavour, water soluble 13.43 Apricot flavour, watersoluble 6.71 Water 26.46 1.2 Color β-Carotene 10% CWS 0.89 Water 67.651.3 Acid and Antioxidant Ascorbic acid 4.11 Citric acid anhydrous 0.69Water 43.18 1.4 Stabilizers Pectin 0.20 Sodium benzoate 2.74 Water 65.601.5 Oil soluble flavours Orange flavour, oil soluble 0.34 Orange oildistilled 0.341.6 Active ingredients

Active ingredients EGCG and RK in the concentrations mentioned above.

Fruit juice concentrates and water soluble flavours are mixed withoutincorporation of air. The color is dissolved in deionized water.Ascorbic acid and citric acid is dissolved in water. Sodium benozoate isdissolved in water. The pectin is added unter stirring and dissolvedwhile boiling. The solution is cooled down. Orange oil and oil solubleflavours are premixed. The active ingredients as mentioned under 1.6 aredry mixed and then stirred preferably into the fruit juice concentratemixture (1.1).

In order to prepare the soft drink compound all parts 3.1.1 to 3.1.6 aremixed together before homogenising using a Turrax and then ahigh-pressure homogenizer (p₁=200 bar, p₂=50 bar).

II. A Bottling Syrup is prepared from the following ingredients: [g]Softdrink compound 74.50 Water 50.00 Sugar syrup 60° Brix 150.00

The ingredients of the bottling syrup are mixed together. The bottlingsyrup is diluted with water to 1 l of ready to drink beverage.

Variations:

Instead of using sodium benzoate, the beverage may be pasteurised. Thebeverage may also be carbonised.

EXAMPLE 5

5 Cereal Bread Typical serving: 50 g Active ingredients:Epigallocatechin gallate (EGCG): 0.3-1250 mg/per serving Raspberryketone (RK): 0.3-1250 mg/per serving Other components: [%] 5 cerealflour 56.8 Water 39.8 Yeast  2.3 Salt  1.1

The yeast is dissolved in a part of the water. All ingredients are mixedtogether to form a dough. Salt is added at the end of the kneading time.After fermentation, the dough is reworked and divided before a loaf isformed. Before baking, the surface of the loaf is brushed with water andsprinkled with flour.

Procedure: Kneading: Spiral kneading system 4 min 1^(st) gear 5 min2^(nd) gear Dough proofing: 60 min Dough temperature: 22-24° C. Proofingtime: 30 min Baking: Oven: Dutch type oven Baking temperature: 250/220°C. Baking time: 50-60 min

EXAMPLE 6

Cookies Type Milano Typical serving: 30 g Active ingredients:Epigallocatechin gallate (EGCG): 0.3-1250 mg/per serving Raspberryketone (RK): 0.3-1250 mg/per serving Other components: [g] Wheat Flour,type 550 41.0 Sugar 20.5 Fat/Butter 20.5 Whole egg (liquid) 18.0 LemonFlavour q.s. Baking agent q.s.

All ingredients are added slowly under mixing to form a sweet shortpastry. Afterwards, the pastry is kept cool (4° C.) for at least 2 hoursbefore flattening the pastry to a thickness of approx. 5 mm. Pieces arecut out and brushed with egg yolk on the surface before baking. Baking:Oven: fan oven Baking temperature: 180° C. Baking time: 15 min

EXAMPLE 7

Toast Typical serving: 100 g Active ingredients: Epigallocatechingallate (EGCG): 0.3-1250 mg/per serving Raspberry ketone (RK): 0.3-1250mg/per serving Other components: [%] Wheat Flour, type 550 55.4 Water33.2 Yeast  2.8 Salt  1.1 Fat/Butter  5.5 Malt  0.6 Emulsifier bakingagent  1.4

The yeast is dissolved in a part of the water. All ingredients are mixedtogether to form a dough. Salt is added at the end of the kneading time.Afterwards, the dough is reworked, divided and placed in a baking tinfor fermentation. After baking, the loaf is unmoulded directly.

Procedure: Kneading: Spiral kneading system 5-6 min 1^(st) gear 3-4 min2^(nd) gear Dough proofing: none Dough temperature: 22-24° C. Proofingtime: 40 min Baking: Oven: Dutch type oven Baking temperature: 220° C.Baking time: 35-40 min

EXAMPLE 8

Yoghurt - set type; 3.5% fat Typical serving: 225 g Active ingredients:Epigallocatechin gallate (EGCG): 0.3-1250 mg/per serving Raspberryketone (RK): 0.3-1250 mg/per serving Other components: [%] Full fat milk(3.8% fat) 90.5  Skimmed milk powder 2.0 Sugar 5.0 Culture 2.5

The milk is heated to 35° C. before addition of milk powder, stabiliser,sugar and active ingredients. This mixture is heated to 65° C. todissolve all ingredients. Then the mixture is homogenized in ahigh-pressure homogenizer (p₁=150 bar, P₂=50 bar) at 65° C. Thisemulsion is then pasteurised at 80° C. for 20 minutes. After cooling to45° C. natural yoghurt/culture is added and mixed. Then this mixture isfilled into cups and fermented at 45° C. for 3-4 hours until a pH of 4.3is reached and then stored at 4° C.

EXAMPLE 9

Yoghurt - stirred type; 3.5% fat Typical serving: 225 g Activeingredients: Epigallocatechin gallate (EGCG): 0.3-1250 mg/per servingRaspberry ketone (RK): 0.3-1250 mg/per serving Other components: [%]Full fat milk (3.8% fat) 90.2  Skimmed milk powder 2.0 Stabiliser 0.3Sugar 5.0 Culture 2.5

The milk is heated to 35° C. before addition of milk powder, stabiliser,sugar and active ingredients. This mixture is heated to 65° C. todissolve all ingredients before homogenisation in a high-pressurehomogenizer (p₁=150 bar, p₂=50 bar) at 65° C. This emulsion is thenpasteurised at 80° C. for 20 minutes. After cooling to 45° C. naturalyoghurt/culture is added and mixed, followed by fermentation at 45° C.for 3-4 hours until a pH of 4.3 is reached. After cooling and stirringvigorously, the yoghurt is filled in cups and stored at 4° C.

EXAMPLE 10

Ice cream; 8% fat Typical serving: 85 g Active ingredients:Epigallocatechin gallate (EGCG): 0.3-1250 mg/per serving Raspberryketone (RK): 0.3-1250 mg/per serving Other components: [g] Milk (3.7%fat) 600.00 Cream (35% fat) 166.00 Skim milk powder 49.10 Sugar 109.00Glucose syrup 80% 70.00 Ice cream stabiliser 5.00 Flavor q.s. Color q.s

Sugar, skim milk powder and stabiliser are added to the milk and cream,mixed and heated to 45° C. Then the colour as stock solution and theglucose syrup is added as well as the active ingredients. The mix isheated up and pasteurized (20 min, 80° C.). Then a homogenization steptakes place. Afterwards the mix is cooled down under constant stirringand the flavour is added at 5° C. The mix maturated at 5° C. during atleast 4 h and then passed through an the ice cream machine (overrun ca.100%). The ice cream is filled into cups and stored at −20 to −30° C.

EXAMPLE 11

Wine gums Active ingredients: Epigallocatechin gallate (EGCG): 0.3-1250mg/per 30 g Raspberry ketone (RK): 0.3-1250 mg/per 30 g Othercomponents: [g] Gelatine 200 Bloom 80.0 Water I 125.0 Sugar crys. 290.0Water II 120.0 Glucose-syrup DE 38 390.0 Citric acid 10.0 Flavour 2.0Colour q.s. Yield ca 1000.0

Disperse gelatine in water I, stir and dissolve by heating over a streambath or using a microwave. Mix sugar with water II and bring to boilinguntil a clear solution is obtained. Remove from heat source. Mix withglucose syrup while dissolved sugar solution is still hot. Slowly addthe gelatine solution. Let rest until foam on surface can be removed and60-65° C. is reached. Add flavour, citric acid and the colour solutionas well as active ingredients under stirring. Deposit into mouldsprinted into starch trays and let sit for at least 48 hours at RT.Remove starch powder and polish with oil or wax Dry at RT and packageinto airtight pouches

EXAMPLE 12

The efficacy of the combination of EGCG and RK as well as of bothcompounds alone on body weight and adiposity was tested in a 4-weekstudy in C57BL6/J mice fed a high fat, high sucrose diet (n=8-11/group).This model of diet-induced obesity and early type 2 diabetes is widelyused to determine the efficacy of anti-obesity compounds.

Male C57BL6/J mice were obtained from Jackson Laboratory (Bar Harbor,Me., USA). Adult mice aged 4 weeks were used in the experiment. Micewere housed individually in plastic cages with bedding and allowed freeaccess to a high fat, high sucrose mouse diet (Kliba # 2154,Klibamuehle, Kaiseraugst, Switzerland) and tap water. The animal roomswere controlled for temperature (24° C.), humidity (55%), and light(12-h light-dark cycle). The animals were randomized into four groups.EGCG and RK were administered as feed-ad-mix. Corn cellulose (2% ofdiet) served as a carrier substance for EGCG and RK as well as a placebowhen used alone. Group 1 received placebo, group 2 received EGCG at adose of 1400 mg/kg body weight (BW)/day, group 3 received RK at a doseof 1400 mg/kg BW/day, and group 4 received the combination of EGCG andRK at a doses of 1400 and 1400 mg/kg BW/day, respectively. Body weightand food intake were determined over the course of the study. All dataare expressed as means for animals in each diet group.

Body weight for each treatment group is shown in Table 1. There was nodifference in food intake between the groups over the study period. Miceon the control diet consumed the same amount of energy as micesupplemented with EGCG, RK or the combined treatment of EGCG+RK. Thedecrease in body weight in comparison to the control group caused byeach treatment was calculated (data are shown in Table 2). The expectedtreatment effect of the combined therapy with EGCG and RK was calculatedby the sum of the effects exerted by monotherapy with EGCG or RK. Thesynergistic factor (SF) is defined as the quotient of the observedeffect and the expected effect. If SF>1, a synergistic effect wasexerted by the combined treatment. TABLE 1 Body weight Initial (g) Week2 (g) Week 4 (g) Control 10.6 20.4 23.6 EGCG (1400 mg/kg BW/day) 11.417.7* 21.4* RK (1400 mg/kg BW/day) 11.5 19.0* 22.1* EGCG + RK 11.2 14.9*18.3* (1400 + 1400 mg/kg BW/day)*significantly different from control (P values less than 0.05 wereconsidered significant)

TABLE 2 Body weight decrease Week 2 (g) Week 4 (g) EGCG (1400 mg/kgBW/day) 2.7 2.2 RK (1400 mg/kg BW/day) 1.6 1.5 Expected (EGCG (1400mg/kg BW/day) + 4.3 3.7 RK (1400 mg/kg BW/day)) Combined treatment 5.5*5.3* EGCG + RK (1400 + 1400 mg/kg BW/day) SF 1.28 1.43*significantly different from expected (P values less than 0.05 wereconsidered significant)

When C57BL6/J mice were fed a high fat, high sucrose diet the bodyweight increased markedly during the 4 week study period. However,dietary supplementation with EGCG or RK resulted in a significantdecrease in body weight compared to control mice withoutsupplementation. The combined treatment with EGCG and RK lead to agreater decrease in body weight than exerted by any monotherapy.Moreover, the decrease in body weight due to the combined treatment wassignificantly greater than the decrease that would be expected by addingthe effects of EGCG and RK. Thus, the effect of the combined treatmentis synergistic as indicated by a SF>1 for week 2 and week 4.

EXAMPLE 13

The efficacy of the combination of EGCG and RK as well as of bothcompounds alone on body weight and adiposity was tested in a 5-weekstudy in C57BLKS/J db/db mice (n=8-9/group). This model of late type 2diabetes with severe hyperglycemia and obesity is widely used todetermine the efficacy of anti-diabetic and anti-obesity compounds.

Male db/db mice were obtained from Jackson Laboratory (Bar Harbor, Me.,USA). Adult mice aged 8 weeks were used in the experiment. Mice werehoused individually in plastic cages with bedding and allowed freeaccess to standard rodent food and tap water. The animal rooms werecontrolled for temperature (24° C.), humidity (55%), and light (12-hlight-dark cycle). The animals were randomized into four groups. EGCGand RK were administered as feed-ad-mix. Corn cellulose (2% of diet)served as a carrier substance for EGCG and RK as well as a placebo whenused alone. Group 1 received placebo, group 2 received EGCG at a dose of1400 mg/kg BW/day, group 3 received RI<at a dose of 1400 mg/kg BW/day,and group 4 received the combination of EGCG and RK at a doses of 1400and 1400 mg/kg BW/day, respectively. Body weight and food intake weredetermined over the course of the study. All data are expressed as meansfor animals in each diet group.

Body weight for each treatment group is shown in Table 3. There was nodifference in food intake between the groups over the study period. Thedecrease in body weight in comparison to the control group caused byeach treatment was calculated (data are shown in Table 4). The expectedtreatment effect of the combined therapy with EGCG and RK was calculatedby the sum of the effects exerted by monotherapy with EGCG or RK. Thesynergistic factor (SF) is defined as the quotient of the observedeffect and the expected effect. If SF>1, a synergistic effect wasexerted by the combined treatment. TABLE 3 Body weight Initial (g) Week2 (g) Week 4 (g) Control 32.2 38.7 38.4 EGCG (1400 mg/kg BW/day) 32.235.7* 37.7 RK (1400 mg/kg BW/day) 32.5 38.4 38.0 EGCG + RK 32.4 33.7*34.3* (1400 + 1400 mg/kg BW/day)*significantly different from control (P values less than 0.05 wereconsidered significant)

TABLE 4 Body weight decrease Week 2 (g) Week 4 (g) EGCG (1400 mg/kgBW/day) 3.0 0.8 RK (1400 mg/kg BW/day) 0.3 0.4 Expected (EGCG (1400mg/kg BW/day) + 3.3 1.2 RK (1400 mg/kg BW/day)) Combined treatment 5.0*4.1* EGCG + RK (1400 + 1400 mg/kg BW/day) SF 1.52 3.42*significantly different from expected (P values less than 0.05 wereconsidered significant)

The db/db model is widely used to determine the efficacy ofanti-diabetic and anti-obesity compounds. As shown in Table 1 these micerapidly develop severe obesity in early life and thereafter reach aplateau in body weight. Dietary supplementation with EGCG resulted in asignificant decrease in body weight at week 2 compared to control micewithout supplementation. Treatment with RK did not significantlydecrease body weight during the study period. After four weeks oftreatment neither EGCG nor RK caused a significant decrease in bodyweight when used as a monotherapy but the combined treatment with EGCGand RK significantly decreased body weight as compared to the untreatedcontrol group. Thus, the combined treatment with EGCG and RK lead to agreater decrease in body weight than exerted by any monotherapy.Moreover, the decrease in body weight due to the combined treatment wassignificantly greater than the decrease that would be expected by addingthe effects EGCG and RK. The combined treatment with EGCG and RK exertedan unexpected synergistic effect on the body weight decrease asindicated by a SF>1 for week 2 and week 4.

1. A nutraceutical composition for the treatment or prevention ofobesity or conditions associated with obesity such asnon-insulin-dependent diabetes mellitus (NIDDM, type II) and syndrome Xcomprising an effective amount of epigallocatechin gallate (EGCG) and4-(4-hydroxyphenyl)-2-butanone (RK).
 2. A composition as in claim 1comprising EGCG in an amount sufficient to administer to a subject about0.01 mg to about 60 mg of EGCG per kg body weight and RK in an amountsufficient to administer to a subject about 0.01 mg to about 60 mg of RKper kg body weight.
 3. A composition as in claim 1 or 2 which is apharmaceutical composition.
 4. A composition as in claim 3 which is asolid pharmaceutical composition comprising about 10 mg to about 500 mgof EGCG and about 10 mg to about 500 mg of RK in a dosage unit.
 5. Acomposition as in claim 3 which is a solid pharmaceutical compositioncomprising about 10 mg to about 50 mg of EGCG and about 10 mg to about50 mg of RK in a dosage unit.
 6. A composition as in claim 1 or 2 whichis a food or beverage or a supplement composition for a food orbeverage.
 7. A method of making a nutraceutical composition for thetreatment or prevention of obesity or conditions associated with obesitysuch as non-insulin-dependent diabetes mellitus (NIDDM, type II) andsyndrome X comprising admixing epigallocatechin gallate (EGCG) and4-(4-hydroxvphenyl)-2-butanone (RK).
 8. A method according to claim 7wherein EGCG is used in an amount sufficient to provide a daily dosageof about 0.01 mg to about 60 mg per body weight of the subject to whichit is to be administered, and RK is used in an amount sufficient toprovide a daily dosage of about 0.01 to about 60 mg per body weight ofthe subject to which it is to be administered.
 9. A method of treatmentor prevention of obesity or conditions associated with obesity such asnon-insulin-dependent diabetes mellitus (NIDDM, type II) and syndrome X,which comprises administering to a subject in need of such treatment aneffective amount of a combination of EGCG and RK.